Dysferlinopathy due to a homozygous DYSF DysF-domain variant in a non-consanguineous Tunisian family.

BACKGROUND: Dysferlinopathies are autosomal recessive neuromuscular disorders caused by pathogenic variants in the DYSF gene, most commonly presenting as limb-girdle muscular dystrophy type R2 (LGMD R2). In this study, we investigated a non-consanguineous Tunisian family with a classical proximal dysferlinopathy phenotype. METHODS AND RESULTS: Two affected male siblings underwent comprehensive clinical and biochemical evaluation, lower-limb magnetic resonance imaging (performed in the proband), whole-exome sequencing, Sanger validation, and segregation analysis. A homozygous missense variant in DYSF, c.2998T > C (p.Ser1000Pro), was identified in both affected siblings, with heterozygous carriage confirmed in both parents. This variant has not been assigned a clinical interpretation. Structural modeling revealed localized disruption of the DysF domain of dysferlin, including steric clashes and loss of hydrogen-bond interactions, findings consistent with impaired protein stability and defective membrane repair. CONCLUSIONS: This study provides the first clinical, structural, and ACMG-based interpretation of the DYSF c.2998T > C (p.Ser1000Pro) variant in Tunisian siblings with LGMD R2, thereby expanding the mutational spectrum of dysferlinopathy.